The Role of Mechanistic Factors in Promoting Chromosomal Translocations Found in Lymphoid and Other Cancers

Zhang, Yu; Gostissa, Monica; Hildebrand, Dominic G.; Becker, Michael; Boboilă, Cristian; Chiarle, Roberto; Lewis, Susanna M.; Alt, Frederick W.

doi:10.1016/s0065-2776(10)06004-9

Cited by 107 publications

(105 citation statements)

References 218 publications

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“…A-EJ has been speculated to be a major contributor to oncogenic translocations (36), possibly because of some specific aspect of the A-EJ pathway or simply reflecting increased DSB persistence (and availability for translocation) in the absence of C-NHEJ (37). Although our studies do not rule out a more dominant role for A-EJ in contributing to oncogenic or other translocation junctions, they clearly suggest that C-NHEJ also can participate in such events.…”

Section: Discussioncontrasting

confidence: 60%

Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells

Schwer

Wei

Chang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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High-throughput, genome-wide translocation sequencing (HTGTS) studies of activated B cells have revealed that DNA double-strand breaks (DSBs) capable of translocating to defined bait DSBs are enriched around the transcription start sites (TSSs) of active genes. We used the HTGTS approach to investigate whether a similar phenomenon occurs in primary neural stem/progenitor cells (NSPCs). We report that breakpoint junctions indeed are enriched around TSSs that were determined to be active by global run-on sequencing analyses of NSPCs. Comparative analyses of transcription profiles in NSPCs and B cells revealed that the great majority of TSS-proximal junctions occurred in genes commonly expressed in both cell types, possibly because this common set has higher transcription levels on average than genes transcribed in only one or the other cell type. In the latter context, among all actively transcribed genes containing translocation junctions in NSPCs, those with junctions located within 2 kb of the TSS show a significantly higher transcription rate on average than genes with junctions in the gene body located at distances greater than 2 kb from the TSS. Finally, analysis of repair junction signatures of TSS-associated translocations in wild-type versus classical nonhomologous end-joining (C-NHEJ)–deficient NSPCs reveals that both C-NHEJ and alternative end-joining pathways can generate translocations by joining TSS-proximal DSBs to DSBs on other chromosomes. Our studies show that the generation of transcription-associated DSBs is conserved across divergent cell types.

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Section: Discussioncontrasting

confidence: 60%

Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells

Schwer

Wei

Chang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The TMPRSS2-ERG rearrangement constitutes the most frequent androgen regulated gene fusion making increased ERG expression an ideal surrogate marker for prostate cancers with an increased risk for developing also other androgen-driven fusions. 34,[36][37][38] It can be speculated that the particularly strong upregulation of NBS1 in ERG-positive tumor cells might thus reflect increased action of the MRN complex for double strand break repair in cancers with a high tendency for fusion gene formation.…”

Section: Early Detection and Diagnosismentioning

confidence: 99%

The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG‐negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression

Grupp

Boumesli

Koop

et al. 2014

Intl Journal of Cancer

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The Nijmegen breakage syndrome (NBS1) gene was suggested as a prostate cancer susceptibility gene. This study was undertaken to determine, whether NBS1 expression is linked to clinically or molecularly relevant subgroups of prostate cancer. NBS1 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancer specimens. NBS1 expression was absent or only weakly detectable in benign prostate. In prostate cancers, NBS1 expression was found in 81.3% of interpretable tumors and was considered strong in 41.3% of cases. NBS1 upregulation was tightly linked to ERG-positive cancers (p < 0.0001). Within ERG-negative cancers, strong NBS1 immunostaining was linked to advanced pathological tumor stage, high Gleason grade, and positive nodal status (p < 0.0001 each), while high NBS1 immunostaining was only weakly associated with advanced pathological tumor stage in ERG-positive cancers (p 5 0.0099). A comparison with chromosomal deletions revealed a strong NBS1 upregulation in PTEN-deleted cancers, while deletions of 3p13, 5q21 and 6q15 did not affect NBS1 expression. High NBS1 expression was linked to biochemical recurrence in ERG-negative and PTEN nondeleted cancers (p < 0.0001), which was largely driven by high KPNA2 karyopherin alpha 2 expression. In conclusion, our study identifies an association of NBS1 expression with surrogates of genomic instability in prostate cancer including TMPRSS2-ERG rearrangements and PTEN deletion. The prognostic impact of NBS1 expression in ERG-negative, PTEN nondeleted cancers was dependent of the expression status of its interaction partner KPNA2.Prostate cancer is the most frequent cancer in men in developed countries and a leading cause of cancer-related death. It is estimated that about 5 to 10% of prostate cancers are hereditary in nature.1 Several genes have recently been identified or suggested as hereditary prostate cancer genes but the relevant genes are still unknown for most hereditary cancers. The high prevalence of sporadic prostate cancer is one of the causes rendering the search for hereditary prostate cancer genes complicated, especially in societies where large families are often small. More than 60% of men older than 60 carry prostate cancer but most of these patients will never face clinical consequences of their disease. The established pre-treatment prognostic parameters Gleason grade, tumor extent on biopsies, preoperative PSA and clinical parameters are statistically powerfull but still insufficent for optimal individual treatment decisions. The identification of these prostate cancers requiring therapy is thus another major need in prostate cancer research.Cancer development and progression is often caused by situations increasing a cell's risk to develop genomic alterations or its ability to repair such DNA alterations. Genes involved in DNA repair mechanisms are thus optimal candidates for affecting cancer progression and have also been identified as the cause for hereditary cancer syndromes such as in hereditary non-polypos...

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“…The hallmark of alt-NHEJ is a more error-prone repair characterized by deletions and unbalanced translocations (24). The viewpoint that alt-NHEJ is the major DNA repair pathway to pathogenic chromosomal errors is further strengthened by the finding that c-NHEJ-deficient mice develop tumors with chromosomal translocations generated by alt-NHEJ (16,25). This implies that the low fidelity alt-NHEJ repair mechanism has critical function in cancer cell survival and in tumor progression.…”

Section: Introductionmentioning

confidence: 99%

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Newman

Bashllari

et al. 2015

Molecular Cancer Research

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In neuroblastoma, MYCN genomic amplification and segmental chromosomal alterations including 1p or 11q loss of heterozygocity and/or 17q gain are associated with progression and poor clinical outcome. Segmental alterations are the strongest predictor of relapse and result from unbalanced translocations attributable to erroneous repair of chromosomal breaks. Although sequence analysis of affected genomic regions suggests that these errors arise by nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB), abnormalities in NHEJ have not been implicated in neuroblastoma pathogenesis. On this basis, the hypothesis that an error-prone mechanism of NHEJ is critical for neuroblastoma cell survival was tested. Plasmid-based DSB repair assays demonstrated efficient NHEJ activity in human neuroblastoma cells with repair products that were error-prone relative to nontransformed cells. Neuroblastoma cells derived from tumorigenic neuroblastic phenotypes had differential DNA repair protein expression patterns compared with nontumorigenic cells. Tumorigenic neuroblastoma cells were deficient in DNA ligase IV (Lig4) and Artemis (DCLRE1C), mediators of canonical NHEJ. Conversely, enzymes required for an error-prone alternative NHEJ pathway (alt-NHEJ), DNA Ligase IIIa (Lig3), DNA Ligase I (Lig1), and PARP1 protein were upregulated. Inhibition of Lig3 and Lig1 led to DSB accumulation and cell death, linking alt-NHEJ to cell survival in neuroblastoma. Neuroblastoma cells demonstrated sensitivity to PARP1 inhibition (PARPi) that paralleled PARP1 expression. In a dataset of human neuroblastoma patient tumors, overexpression of genes encoding alt-NHEJ proteins associated with poor survival.Implications: These findings provide an insight into DNA repair fidelity in neuroblastoma and identify components of the alt-NHEJ pathway as promising therapeutic targets. Mol Cancer Res; 13(3); 470-82. Ó2015 AACR.

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The Role of Mechanistic Factors in Promoting Chromosomal Translocations Found in Lymphoid and Other Cancers

Cited by 107 publications

References 218 publications

Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells

Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells

The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG‐negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

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